Adult: For the treatment of mild to moderate cases in nonhospitalised patients with confirmed positive SARS-CoV-2 diagnostic test results who do not require supplemental oxygen and are at increased risk of progression to severe COVID-19, including hospitalisation: Nirmatrelvir tablets are co-packaged with a ritonavir tablet in each blister card. Nirmatrelvir should be co-administered with ritonavir; failure to correctly co-administer both drugs may lead to insufficient nirmatrelvir plasma levels required to achieve the desired therapeutic effect. Recommended dose: 300 mg (two 150 mg tablets) nirmatrelvir to be taken together with 100 mg (one tablet) ritonavir bid for 5 days. Initiate therapy as soon as possible following diagnosis of COVID-19 and within 5 days of symptom onset. Safety and efficacy of therapy beyond 5 consecutive days have not been established. Missed dose: If a dose is missed within 8 hours of the time it is usually taken, take the missed dose as soon as possible then return to the normal dosing schedule. If the dose is missed by >8 hours, skip the missed dose and instead take the next dose at the usual dosing schedule. Do not double the dose to make up for a missed dose. Child: For the treatment of mild to moderate cases in nonhospitalised patients with confirmed positive SARS-CoV-2 diagnostic test results who are at increased risk of progression to severe COVID-19, including hospitalisation: ≥12 years weighing at least 40 kg: Same as adult dose. Elderly: Same as adult dose.
Renal Impairment
Severe (eGFR <30 mL/min): Not recommended until more data are available. Moderate (eGFR ≥30 to <60 mL/min): Reduce dose to 150 mg (one tablet) nirmatrelvir to be taken together with 100 mg (one tablet) ritonavir bid for 5 days. Mild (eGFR ≥60 to <90 mL/min): No dosage adjustment required.
Hepatic Impairment
Mild to moderate (Child-Pugh class A to class B): No dosage adjustment required. Severe (Child-Pugh class C): Currently, pharmacokinetic or safety data of giving nirmatrelvir with ritonavir in patients with severe hepatic impairment have not been established; until such data are available, use in these patients is not recommended.
Administration
May be taken with or without food. Swallow whole, do not chew/break/crush.
Contraindications
History of clinically significant hypersensitivity reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis) to nirmatrelvir or ritonavir. Concomitant use with drugs that are highly dependent on CYP3A isoenzyme for clearance and for which increased concentrations are associated with serious adverse reactions (e.g. alfuzosin, pethidine, propoxyphene, piroxicam, ranolazine, amiodarone, bepridil, dronedarone, propafenone, quinidine, flecainide, neratinib, venetoclax, ibrutinib, colchicine, clozapine, lurasidone, pimozide, dihydroergotamine, ergotamine, methylergonovine, lovastatin, simvastatin, lomitapide, astemizole, terfenadine, cisapride, fusidic acid, oral midazolam, triazolam, diazepam, estazolam, flurazepam, avanafil, sildenafil [when used for pulmonary arterial hypertension]). Concurrent use with potent CYP3A inducers (e.g. apalutamide, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort).
Special Precautions
Patient with pre-existing liver enzyme abnormalities, hepatitis, or liver diseases. Co-administration of nirmatrelvir with ritonavir (HIV-1 protease inhibitor) may increase the risk of developing HIV-1 protease inhibitor resistance in individuals with uncontrolled or undiagnosed HIV-1 infection. Patients taking other ritonavir- or cobicistat-containing HIV or hepatitis C virus (HCV) regimens must continue their therapy as indicated; no dosage adjustment is needed when nirmatrelvir with ritonavir is co-administered with other products containing ritonavir or cobicistat. Renal and hepatic impairment. Children. Pregnancy and lactation; use only if potential benefits justify potential risks as there is limited data regarding the use of nirmatrelvir with ritonavir in pregnant and lactating women.
It should be noted that:
- Use of nirmatrelvir with ritonavir for the treatment of COVID-19 have not been fully established, some data are available from several initial clinical trials in the US and other countries.
- According to microbiological studies, nirmatrelvir has shown antiviral activity against SARS-CoV-2 (USA-WA1/2020 isolate) infection of differentiated normal human bronchial epithelial (dNHBE) cells, a primary human lung alveolar epithelial cell line, following 3 days of drug exposure. Additionally, it exhibited similar cell culture antiviral activity against SARS-CoV-2 isolates belonging to Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Mu (B.1.621), and Omicron (B.1.1.529/BA.1) variants where the Beta (B.1.351) variant was the least susceptible tested variant (approx 3-fold reduced susceptibility relative to the USA-QA1/2020 isolate). Data on the antiviral activity of nirmatrelvir evolve through time as clinical trials are being conducted continuously. For more information on the antiviral activity of nirmatrelvir, refer to the latest local guidelines.
- Nirmatrelvir co-packaged with ritonavir may be available for use in some countries under emergency use authorisation (EUA) or conditional approval. Registration status and/or availability may vary between countries.
- The safety and efficacy of nirmatrelvir with ritonavir for the treatment of mild to moderate cases of COVID-19 continue to be evaluated. Preliminary clinical trial data showed that the use of nirmatrelvir with ritonavir early in the disease process when viral loads are high provided maximum benefit and reduced the risk of hospitalisation and/or death when given within 5 days of onset of symptoms.
- Currently available COVID-19 treatment guidelines recommend limiting the use of nirmatrelvir with ritonavir to nonhospitalised patients with mild to moderate cases who are at high risk of progression to severe COVID-19, including hospitalisation. If the patient requires hospitalisation due to severe or critical COVID-19 after treatment initiation, the remainder of the full 5-day treatment course may be completed per the discretion of the healthcare provider.
- Nirmatrelvir with ritonavir is not indicated for use as pre-exposure or postexposure prophylaxis of COVID-19.
- Completion of the recommended full 5-day treatment course and continued isolation in accordance with the local public health guidelines are important to maximise viral clearance and minimise SARS-CoV-2 transmission.
For healthcare professionals:
- Refer to the local health authority for the most up-to-date information when prescribing nirmatrelvir with ritonavir.
- Nirmatrelvir with ritonavir has significant and complex drug-drug interactions, mainly due to the ritonavir component. Consider the potential for drug interactions before initiation and during nirmatrelvir with ritonavir treatment. Carefully review the patient's concomitant medications during therapy (including over-the-counter and herbal medicines) and monitor for adverse effects associated with the use of concomitant agents. The risk of interactions with concurrent medications during the full 5-day treatment period for nirmatrelvir with ritonavir must be weighed against the benefits of receiving the therapy. For a more detailed list of all possible drugs that may interact with nirmatrelvir with ritonavir, may consider referring to local treatment guidelines and specific product information of ritonavir.
- To alleviate the risks of this unapproved drug during pandemic use, local regulatory agencies may require healthcare providers to comply with certain regulations on the use of nirmatrelvir with ritonavir. Please refer to respective local regulatory agencies for further information.
PO: Z (Ritonavir-boosted nirmatrelvir is not recommended during pregnancy unless the benefits outweigh the risks.)
Patient Counseling Information
Individuals using combined hormonal contraceptives must use an effective alternative birth control method or an additional barrier method of contraception during therapy and until after 1 complete menstrual cycle after discontinuing nirmatrelvir with ritonavir treatment.
Monitoring Parameters
Evaluate renal and hepatic function prior to treatment initiation. Monitor for signs and symptoms of potential adverse reactions, particularly in patients concurrently taking other drugs.
Drug Interactions
May increase the plasma concentrations of amphetamine, afatinib, systemic lidocaine, trazodone, ketoconazole, itraconazole, erythromycin, rifabutin, amprenavir, atazanavir, darunavir, efavirenz, maraviroc, quetiapine, amlodipine, diltiazem, digoxin, bosentan, sofosbuvir/velpatasvir/voxilaprevir, imipramine, sertraline, paroxetine, haloperidol, risperidone, thioridazine, atorvastatin, rosuvastatin, ciclosporin, tacrolimus, salmeterol, fentanyl, parenteral midazolam, vorapaxar. Increased risk of bleeding with rivaroxaban. May decrease the plasma concentrations of bupropion, warfarin, ethinylestradiol, methadone, morphine, theophylline, atovaquone, zidovudine. Increased risk of Cushing's syndrome and adrenal suppression with budesonide, fluticasone and triamcinolone. May reduce the efficacy of combined hormonal contraceptives. Potentially Fatal: Nirmatrelvir with ritonavir increases the plasma concentrations of agents primarily metabolised by CYP3A (e.g. alfuzosin, pethidine, propoxyphene, piroxicam, ranolazine, amiodarone, bepridil, dronedarone, flecainide, propafenone, quinidine, neratinib, venetoclax, ibrutinib, colchicine, clozapine, lurasidone, pimozide, ergotamine, methylergonovine, dihydroergotamine, lovastatin, simvastatin, lomitapide, astemizole, terfenadine, cisapride, fusidic acid, oral midazolam, triazolam, diazepam, estazolam, flurazepam, avanafil, sildenafil [when used for pulmonary arterial hypertension]) which may result in serious adverse effects. Potent CYP3A inducers (e.g. apalutamide, carbamazepine, phenobarbital, phenytoin, rifampicin) significantly decrease the plasma levels of nirmatrelvir and ritonavir which may lead to reduced therapeutic effect and possible viral resistance development; treatment initiation of nirmatrelvir with ritonavir must be delayed after the discontinuation of the potent CYP3A inducers due to the delayed offset of the CYP3A inducer.
Food Interaction
St. John's wort significantly decreases the plasma levels of nirmatrelvir and ritonavir which may lead to reduced therapeutic effect and possible viral resistance development; treatment initiation of nirmatrelvir with ritonavir must be delayed after the discontinuation of St. John's wort due to the delayed offset of St. John's wort.
Action
Description: Nirmatrelvir, an investigational antiviral agent, is a peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), also known as 3C-like protease (3CLpro) or nsp5 protease. The inhibition of SARS-CoV-2 Mpro prevents the processing of polyprotein prescursors, thereby blocking the viral replication. Ritonavir, an HIV-1 protease inhibitor, has no activity against SARS-CoV-2 Mpro. However, it acts as a pharmacokinetic enhancer by inhibiting the CYP3A-mediated metabolism of nirmatrelvir leading to increased nirmatrelvir plasma concentrations. Pharmacokinetics: Absorption: Time to peak plasma concentration: Nirmatrelvir when given with ritonavir: 3 hours (range: 1.02-6 hours). Distribution: Plasma protein binding: 69% (nirmatrelvir when given with ritonavir). Metabolism: Minimal metabolism (nirmatrelvir when given with ritonavir). Excretion: Nirmatrelvir when given with ritonavir: Via urine; faeces. Elimination half-life: 6.05 ± 1.79 hours (nirmatrelvir when given with ritonavir).
Chemical Structure
Nirmatrelvir Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 155903259, Nirmatrelvir. https://pubchem.ncbi.nlm.nih.gov/compound/Nirmatrelvir. Accessed Mar. 29, 2022.
Storage
Store between 20-25°C. Do not refrigerate or freeze.
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